Structural chemistry of inhibitor binding to Aldose Reductase: An integrated approach combining subatomic resolution crystallography, microcalorimetry, multipolar modeling and quantum modeling

• Applicant: Professor Dr. Gerhard Klebe
• Subject Area: Pharmacy
• Term: from 2002 to 2008
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5382933

This project involves four laboratories, situated at the IGBMC, Strasbourg; the University of Marburg; the University of Nancy and the University of Goettingen. The overall purpose of the project is to study the binding of inhibitors to Aldose Reductase (AR), a protein involved in diabetic complications, and to develop state of the art methodology in order to fulfill this task. It goes from the experimental data from subatomic resolution crystallographic studies of AR-inhibitor complexes (Strasbourg) and microcalorimetric studies of AR-inhibitor binding (Marburg) to binding energy calculations issued from the quantum modeling of inhibitor binding (Nancy and Strasbourg). The project needs state of the art refinement technology, to be provided by the Goettingen group for anisotropic refinement of spherical atoms and by the Nancy group for multipolar modeling. These groups have already started a collaboration on the complex of AR-IDD594 inhibitor, of which data has been collected to a resolution of 0.66 Å ( the highest ever recorded for a protein of this size). The AR-IDD594 complex has already shown the inhibitor binding mode in the active site and the specificity pocket. It is planned to continue this work on three other inhibitors: 393, 509 and 860, which produce complex crystals capable of atomic resolution diffraction. The data of these inhibitors will be measured, the structures will be refined, and multipolar and quantum calculations will be done. Charge states of the inhibitor and of the protein residues binding the inhibitor will be determined from these refinements. Energy perturbation calculations will provide information about the difference in binding energies between the different inhibitors, which will be correlated with the microcalorimetric data. The end result will be a detailed understanding of the inhibitor binding energies, very useful for drug design studies, and advances in the crystallographic and modeling methods.

• DFG Programme: Research Grants
• International Connection: France
• Participating Persons: Professor Dr. Claude Lecomte; Dr. Alberto Podjarny